← Product Code NIQ · P170008

# EluNIR™ Ridaforolimus Eluting Coronary Stent System (P170008)

_Medinol, Ltd. · NIQ · Nov 28, 2017 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P170008

## Device Facts

- **Applicant:** Medinol, Ltd.
- **Product Code:** NIQ
- **Decision Date:** Nov 28, 2017
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The EluNIR™ Ridaforolimus Eluting Coronary Stent System is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo lesions ≤30mm in length in native coronary arteries with reference diameters of 2.50mm to 4.25mm.

## Device Story

EluNIR is a drug-eluting coronary stent system comprising a cobalt-chromium (CoCr) alloy stent pre-mounted on a rapid exchange (RX) delivery catheter. The stent is coated with a polymer blend (PBMA and CarboSil® 20 55D) loaded with the immunosuppressant drug ridaforolimus. Used in cardiac catheterization labs by interventional cardiologists to treat coronary artery disease; the device is delivered via guidewire to the target lesion and expanded via balloon inflation. The drug coating inhibits neointimal growth by arresting cell cycle at the G1 stage. The system provides mechanical scaffolding to maintain luminal diameter while the drug release mitigates restenosis. Clinical benefit includes improved coronary blood flow and reduced need for target lesion revascularization.

## Clinical Evidence

Evidence from the BIONICS trial (n=1919, randomized 1:1 vs. Resolute) and BIONICS-PK study. Primary endpoint (TLF at 1 year) was 5.4% for both groups (p=0.0013 for non-inferiority). Angiographic sub-study (n=202) showed in-stent late loss of 0.22mm (EluNIR) vs 0.23mm (Resolute) at 13 months. IVUS sub-study (n=155) showed percent NIH of 8.10% (EluNIR) vs 8.85% (Resolute). NIREUS trial (n=305) also supported non-inferiority for late lumen loss.

## Technological Characteristics

Stent: L-605 Cobalt Chromium alloy (ASTM F90). Coating: PBMA and CarboSil® 20 55D polymers with ridaforolimus (1.1 μg/mm²). Delivery: Rapid Exchange (RX) balloon-expandable catheter. Dimensions: 2.5-4.0mm diameter, 8-33mm length. Sterilization: Ethylene Oxide (EO). Connectivity: None (mechanical device).

## Regulatory Identification

Stent, coronary, drug-eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen.  The drug coating is intended to inhibit restenosis.

## Predicate Devices

- NIRxcell CoCr Coronary Stent on RX System ([P110004](/device/P110004.md))

## Reference Devices

- Cypher drug eluting stent ([P020026](/device/P020026.md))
- XIENCE PRIME drug eluting stent ([P110019](/device/P110019.md))
- AxioMed Freedom Lumbar Disc
- Freedom Cervical Disc
- X-Suit NIR Biliary Metallic Stent
- NIRFLEX stent ([P020040](/device/P020040.md))
- Resolute Zotarolimus-Eluting Stent System

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug Eluting Coronary Stent System
Device Trade Name: EluNIR™ Ridaforolimus Eluting Coronary Stent System
Device Procode: NIQ
Applicant's Name and Address: Medinol LTD
Kiryat Atidim, Building 8
POB 58165
Tel Aviv 6158101
Israel
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P170008
Date of FDA Notice of Approval: November 28, 2017

II. INDICATIONS FOR USE

The EluNIR™ Ridaforolimus Eluting Coronary Stent System is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo lesions ≤30mm in length in native coronary arteries with reference diameters of 2.50mm to 4.25mm.

III. CONTRAINDICATIONS

Coronary artery stenting is generally contraindicated in the following patient types:

- Patients who cannot receive recommended antiplatelet and/or anticoagulation therapy.
- Patients judged to have a lesion which prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery system.
- Patients with hypersensitivity or allergies to aspirin, heparin, clopidogrel, ticlopidine, drugs such as ridaforolimus or similar drugs, the polymer or its indicvidual copmonents CarboSil® 20 55D (Thermoplastic Silicone-Polycarbonate-urethane) and Poly n-Butyl Methacrylate (PBMA), cobalt, chromium, nickel, molybdenum, or contrast media.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the EluNIR™ Ridaforolimus Eluting Coronary Stent System labeling.

V. DEVICE DESCRIPTION

The EluNIR Ridaforolimus Eluting Coronary Stent System is a single use device/drug combination product comprising the following components:

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1. Device Components (Section V.A):

1.1 Stent: Cobalt Chromium (CoCr) alloy
1.2 Delivery System: Rapid Exchange (RX) Coronary System

2. Drug Components (Coating Formulation):

2.1 Drug (the active pharmaceutical ingredient (API)):

Ridaforolimus CAS Registry Number: 572924-54-0 (formerly Deforolimus and AP23573) Section V.B1

2.2 Polymer Coating Blend (Inactive Ingredients, Section V.B2): Poly n-Butyl Methacrylate (PBMA), Section V.B2.1 CarboSil® 20 55D (CS), Section V.B2.2

Table 1 describes the characteristics of the  $\mathrm{EluNIR}^{\mathrm{TM}}$  stent system.

Table 1: EluNIR Ridaforolimus Eluting Coronary Stent System: Product Description

|  Available Stent Lengths (mm) | 8, 12, 15, 17, 20, 24, 28, 33  |   |
| --- | --- | --- |
|  Available Stent Diameters (mm) | 2.5, 2.75, 3.0, 3.5, 4.0  |   |
|  Stent Material | A medical grade L-605 Cobalt Chromium (CoCr), annealed, ASTM F90  |   |
|  Drug Component | A coating of polymers loaded with ridaforolimus in a formulation applied to the entire surface of the stent at a dose of approximately 1.1 μg/mm2which results in a maximum nominal drug content of 219μg on the largest stent (4.0mm x 33mm)  |   |
|  Delivery System Working Length | 140cm  |   |
|  Delivery System Design | Single access port to inflation lumen; guidewire exit notch (RX-Port) is located 30cm from distal tip; designed for guidewires ≤ 0.014" (0.36mm)  |   |
|  Stent Delivery System | Expandable balloon with two (2) radiopaque markers located on the catheter system balloon shaft to indicate balloon positioning and expanded stent length  |   |
|  Balloon Inflation Pressure | For all diameters: Nominal Pressure: 10atm (1013 kPa) Rated Burst Pressure (RBP): 18atm (1824 kPa)  |   |
|  Minimum Guiding Catheter Inner Diameter | ≥5F (0.056"/1.42mm)  |   |
|  Catheter Shaft Outer Diameter | Proximal | 2.1F (0.69mm)  |
|   |  Distal | 2.7F (0.90mm) for products of 8mm - 28mm length  |
|   |   |  2.9F (0.97mm) for products of 33mm length  |

# A. Device Component Description

The  $\mathrm{EluNIR}^{\mathrm{TM}}$  device component consists of a ridaforolimus eluting coronary stent pre-mounted onto an RX delivery system. The stents are made from a cobalt-based alloy and are coated with a drug/polymer coating, which consists of a Poly n-Butyl Methacrylate (PBMA) polymer, a CarboSil®20 55D polymer and the active pharmaceutical ingredient (API), ridaforolimus. The  $\mathrm{EluNIR}^{\mathrm{TM}}$  delivery system provides a means of delivering the stent through the coronary vasculature and, once in the desired location, expands the stent through balloon inflation.

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The  $\mathrm{EluNIR}^{\mathrm{TM}}$  uncoated (bare metal) stent and delivery system are identical to Medinol's PMA approved NIRxcellTM CoCr Coronary Stent on RX System (P110004 and its supplements).

# B. Drug Component Description

The drug coating on the  $\mathrm{EluNIR}^{\mathrm{TM}}$  stent consists of a Polymer Coating Blend [Poly n-Butyl Methacrylate (PBMA) and CarboSil®20 55D, (inactive ingredients)], and the active pharmaceutical ingredient (API) ridaforolimus.

# B1. Ridaforolimus

Ridaforolimus (CAS Registry Number: 572924-54-0, formerly Deforolimus and AP23573) is the active pharmaceutical ingredient in the  $\mathrm{EluNIR}^{\mathrm{TM}}$  stent. It is a member of the limus family of drugs, a unique, non-prodrug analog of rapamycin (also referred to as sirolimus), a natural macrocyclic lactone, which is a fermentation product of Streptomyces hygroscopicus. Like rapamycin, ridaforolimus is an immunosuppressant.

Table 2 provides the nominal dose of ridaforolimus per nominal stent length/diameter for the product matrix. The drug load for all stent designs is  $1.1\mu \mathrm{g} / \mathrm{mm}^2$  of ridaforolimus.

Ridaforolimus is a clean, white to off-white amorphous powder that is freely soluble in acetone, ethanol, tetrahydrofuran, and acetonitrile. It is insoluble in heptane. Ridaforolimus has 15 chiral centers. The molecular formula is C53H84NO14P and the molecular weight/mass is  $990.22\mathrm{g / mol}$ .

![img-0.jpeg](img-0.jpeg)
Figure 1 illustrates the chemical structure of ridaforolimus.
Figure 1: Chemical structure of ridaforolimus

# B2. Inactive Ingredients (Polymer Coating Blend)

The bare metal stent is coated with a polymer blend consisting of CarboSil® 20 55D and Poly n-Butyl Methacrylate (PBMA), (55%w/45%w respectively), combined with the drug ridaforolimus.

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# B2.1 PBMA

PBMA is a biocompatible homopolymer of n-Butyl Methacrylate from the Acrylic family.

PBMA is known for a variety of biomedical uses: in ophthalmological devices (contact lenses, crystalline lenses); for odonatological applications (maxillofacial prostheses, mouth guards); in combination with other biomedical elastomers (polyurethanes, SEBS, etc.) to produce linear and graft copolymers; and as a component of the coating formulation of the following PMA approved drug eluting stents: Cypher™ drug eluting stent (Cordis, USA, PMA P020026) and XIENCE PRIME drug eluting stent (Abbott, USA, PMA P110019).

PBMA is a white amorphous solid that is soluble in ethyl acetate, tetrahydrofuran, chloroform, methylene chloride, acetone, and toluene, and sparingly soluble in alcohols – methanol, isopropanol. The molecular formula is [CH2CH2(CH3)(COOC4H9)] and the molecular weight/mass is 220-380g/mol.

![img-1.jpeg](img-1.jpeg)
Figure 2 illustrates the polymer chemical structure.
Figure 2: Chemical Structure of PBMA

# B2.2 CarboSil® 20 55D UR Thermoplastic Silicone-Polycarbonate-urethane with SME®

CarboSil® 20 55D is a medical grade copolymer.

CarboSil® TSPCU is used in a wide range of medical applications, including the CE-marked nervous system electrostimulation (AxioMed Freedom®Lumbar Disc and Freedom® Cervical Disc); the biliary covered stent (X-Suit NIR® Biliary Metallic Stent); and other typical medical applications, including leads, grafts, balloons, shunts, and cardio-assist devices.

Numerous studies have demonstrated that CarboSil® is both biocompatible and safe for its intended use. The expected chemical additives and degradation products from CarboSil® and other polyurethanes have been thoroughly studied and reported in peer reviewed publications $^{1-7}$ . The molecular formula is: SiC3H9O-(SiC2H6)p-SiC2H6-Ri-O-{(C15H12N2O2)-O-(RjCO3)n-RjO}x-C15H12N2O2-[C4H8O2-C15H12N2O2]y}z-SiC2H6O2Ri-([SiC2H6)pSiC3H9

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The molecular weight/mass is  $\geq 200\mathrm{g / mol}$ . Figure 3 illustrates CarboSil® 20 55D chemical structure.

![img-2.jpeg](img-2.jpeg)
Figure 3: Chemical structure of CarboSil® 20 55D

The EluNIR Ridaforolimus Eluting Coronary Stent System is available in multiple stent sizes (diameters and lengths), containing a range nominal drug doses, as listed in Table 2.

Table 2: Product matrix and Nominal Total Dose of Ridaforolimus (μg) per Nominal Stent Length and Diameter

|  Product Catalog Number | Nominal Expanded Stent ID (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Ridaforolimus Content (μg)  |
| --- | --- | --- | --- |
|  LUN250R08US | 2.50 | 8 | 34  |
|  LUN250R12US | 2.50 | 12 | 50  |
|  LUN250R15US | 2.50 | 15 | 66  |
|  LUN250R17US | 2.50 | 17 | 74  |
|  LUN250R20US | 2.50 | 20 | 89  |
|  LUN250R24US | 2.50 | 24 | 104  |
|  LUN250R28US | 2.50 | 28 | 120  |
|  LUN250R33US | 2.50 | 33 | 144  |
|  LUN275R08US | 2.75 | 8 | 46  |
|  LUN275R12US | 2.75 | 12 | 67  |
|  LUN275R15US | 2.75 | 15 | 87  |
|  LUN275R17US | 2.75 | 17 | 98  |
|  LUN275R20US | 2.75 | 20 | 119  |
|  LUN275R24US | 2.75 | 24 | 140  |
|  LUN275R28US | 2.75 | 28 | 160  |
|  LUN275R33US | 2.75 | 33 | 192  |
|  LUN300R08US | 3.00 | 8 | 46  |
|  LUN300R12US | 3.00 | 12 | 67  |

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|  Product Catalog Number | Nominal Expanded Stent ID (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Ridaforolimus Content (μg)  |
| --- | --- | --- | --- |
|  LUN300R15US | 3.00 | 15 | 87  |
|  LUN300R17US | 3.00 | 17 | 98  |
|  LUN300R20US | 3.00 | 20 | 119  |
|  LUN300R24US | 3.00 | 24 | 140  |
|  LUN300R28US | 3.00 | 28 | 160  |
|  LUN300R33US | 3.00 | 33 | 192  |
|  LUN350R08US | 3.50 | 8 | 53  |
|  LUN350R12US | 3.50 | 12 | 83  |
|  LUN350R15US | 3.50 | 15 | 98  |
|  LUN350R17US | 3.50 | 17 | 113  |
|  LUN350R20US | 3.50 | 20 | 128  |
|  LUN350R24US | 3.50 | 24 | 158  |
|  LUN350R28US | 3.50 | 28 | 189  |
|  LUN350R33US | 3.50 | 33 | 219  |
|  LUN400R08US | 4.00 | 8 | 53  |
|  LUN400R12US | 4.00 | 12 | 83  |
|  LUN400R15US | 4.00 | 15 | 98  |
|  LUN400R17US | 4.00 | 17 | 113  |
|  LUN400R20US | 4.00 | 20 | 128  |
|  LUN400R24US | 4.00 | 24 | 158  |
|  LUN400R28US | 4.00 | 28 | 189  |
|  LUN400R33US | 4.00 | 33 | 219  |

# C. Mechanism of Action

The mechanism by which the EluNIR Ridaforolimus stent inhibits neointimal growth as seen in pre-clinical and clinical studies has not been established. At the cellular level, ridaforolimus inhibits growth factor-stimulated cell proliferation. At the molecular level, ridaforolimus forms a complex with the cytoplasmic protein FKBP-12 (FK 506 Binding Protein). This complex binds to and interferes with FKBP-12 Rapamycin Associated Protein (FRAP), also known as mammalian target of rapamycin (mTOR), leading to inhibition of cell metabolism, growth, and proliferation by arresting the cell cycle at the late G1 stage.

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# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of patients with coronary artery disease, including exercise, diet, drug therapy, percutaneous coronary interventions (i.e., balloon angioplasty, atherectomy, bare metal stents, coated stents, and other drug-eluting stents), and coronary artery bypass grafting (CABG) surgery. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

# VII. MARKETING HISTORY

Table 3 lists countries where the product is currently commercially available. No products have been withdrawn from the market in any country for any reason.

Table 3: Countries with EluNIR™ Ridaforolimus Eluting Coronary Stent System Commercial availability

|  • Austria | • Estonia | • Luxembourg | • Sweden  |
| --- | --- | --- | --- |
|  • Belgium | • Finland | • Malta | • United Kingdom  |
|  • Bulgaria | • Germany | • Netherlands | • Iceland  |
|  • Cyprus | • Hungary | • Romania | • Liechtenstein  |
|  • Czech Republic | • Ireland | • Slovenia | • Norway  |
|  • Denmark | • Italy | • Spain | • Switzerland  |

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the EluNIR Ridaforolimus Eluting Coronary Stent System.

Adverse events (in alphabetical order) which may be associated with percutaneous coronary and treatment procedures, where coronary stents are used in native coronary arteries include, but are not limited to:

- Access site complicationsᵃ
- Acute myocardial infarction
- Allergic reaction or hypersensitivity to stent components or contrast media
- Aneurysm
- Angina pectoris
- Anxiety
- Bleeding complications which may require transfusions or surgical repair
- Need for CABG- emergent or non-emergent
- Cardiac arrhythmias
- Cardiac failure
- Cardiac tamponade
- Cardiac shock
- Coronary artery complicationsᵇ
- Death
- Delayed endothelialization

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- Distal emboli
- Endocarditis
- Failure to deliver the stent to the intended site
- Fever or pyrogenic reactions
- Hypertension
- Hypotension
- Infections
- Myocardial ischemia
- Nausea and vomiting
- Palpitations
- Perforation of the heart or great vessels
- Pericardial effusion
- Pulmonary failure
- Renal failure
- Stent compression
- Stent misplacement / migration / embolization
- Stent thrombosis
- Stroke / cerebrovascular accident (CVA) / transient ischemic attack (TIA)
- Vasovagal reaction
- Ventricular fibrillation
- Vessel Spasm
- Volume overload

a Includes arteriovenous fistula, hematoma, infection, nerve injury, pain, peripheral ischemia, phlebitis, pseudoaneurysm
b Includes abrupt closure, dissection, embolism, injury, perforation, plaque rupture/shift, restenosis, rupture, spasm, thrombosis, total occlusion

Patient exposure to ridaforolimus is directly related to the total surface area of stents implanted. The actual side effects/complications that may be associated with the use of ridaforolimus in the setting of drug eluting stents (DES) are not fully known.

The adverse events that have been associated with the intravenous injection of ridaforolimus in humans are based on experience with the drug in phase I oncology based studies conducted by Merck Sharp & Dohme Corp. and Ariad Pharmaceuticals Inc. where there is systemic exposure in concentrations that are 150 times greater than foreseeable with the EluNIR stent.

Potential adverse events (AEs) and adverse drug events (ADEs) for systemic exposure of ridaforolimus include, but are not limited to:

- Anemia
- Anorexia
- Alopecia
- Aspartate Aminotransferase increased
- Blood Creatine phosphokinase

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- Blood Alkaline Phosphatase increased
- Constipation
- Dehydration
- Diarrhea
- Dysgeusia
- Dermatitis acneiform
- Febrile neutropenia
- Fatigue
- Hyperglycemia
- Hypertriglyceridemia
- Hypokalaemia
- Hypercholesterolaemia
- Hypophosphataemia
- Leukopenia
- Mucosal inflammation
- Nausea
- Nail disorder
- Pneumonia
- Pneumonitis
- Pyrexia
- Pruritus
- Paraesthesia
- Renal failure acute
- Rash
- Stomatitis
- Thrombocytopenia
- Vomiting
- Weight decrease

There may be other potential adverse events that are unforeseen at this time.

For the specific adverse events that occurred in the clinical studies, please see Section X below.

## IX. SUMMARY OF NON-CLINICAL STUDIES

A series of non-clinical laboratory studies and pharmacokinetic studies related to the product were performed. Studies included those performed on the drug substance (i.e., ridaforolimus), the coated stent alone, the polymer-only coated stent alone, the delivery system, and the finished combination products (i.e., EluNIR Ridaforolimus-Eluting Coronary Stent System).

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# A. Laboratory Studies

# A1. In Vitro Engineering Testing

In vitro engineering testing, in accordance with FDA's "Guidance for Industry and FDA Staff:

Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems" (April, 2010), was conducted on the EluNIR stent. Some in vitro engineering tests were performed on the uncoated, bare metal version of the EluNIR stent, since there was no change to the stent substrate. An appropriate rationale was provided where the testing of the bare metal stent provided a worst case representative condition for the attributes evaluated. The effect of the coating is assumed to be negligible when evaluated against measurement and manufacturing tolerances. Supplementary in vitro engineering tests were also performed on the EluNIR delivery systems containing the EluNIR stent mounted on a delivery catheter.

Table 4 summarizes this testing. "Pass" denotes that the test results met product specifications and/or the recommendations in the above referenced guidance document.

Additional tests were conducted to support the integrity of the coating on the EluNIR™ Ridaforolimus Eluting Coronary Stent System and are summarized separately in Section IX.A2.

Table 4: In vitro engineering testing supporting performance of EluNIR Stent and Delivery System

|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Material Characterization  |   |   |   |
|  Bare Metal Stent Material Analysis – Chemical Composition | This test was conducted on a CoCr L605 sheet provided by material supplier prior to any processing to confirm that chemical composition is in accordance with ASTM F90. The test confirmed that EluNIR bare metal stents are produced from material that conforms in chemical composition to ASTM F90. | A medical grade L-605 CoCr alloy sheet | Pass  |
|  Bare Metal Stent Material Analysis – Mechanical Properties (Tensile Strength and Elongation) | This test was performed on the metal stent source material (CoCr L605 sheet) prior to any processing. The tensile and yield strength and elongation met acceptance criteria. | A medical grade L-605 CoCr alloy sheet  |   |
|  Delivery System Material Analysis | Raw material lots are not released prior to successfully passing the tests detailed in incoming inspection procedures. | EluNIR Stent System | Pass  |
|  Stent Dimensional and Functional Attributes  |   |   |   |
|  Pitting Corrosion | This test was conducted according to ISO 25539-2 and ASTM F2129 on EluNIR stents to confirm that they possess sufficient Pitting Corrosion resistance. Results met acceptance criteria and demonstrate sufficient Pitting Corrosion resistance. | EluNIR Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Fretting and Crevice Corrosion | This test was conducted according to ISO 25539-2 and ASTM F2129 on EluNIR stents following accelerated durability testing in overlapped stent conditions to determine potential for Fretting and Crevice Corrosion. The results met acceptance criteria and indicate that the stents possess a high resistance to Fretting and Crevice Corrosion. | EluNIR Stents | Pass  |
|  Galvanic Corrosion | This test was conducted according to ISO 25539-2, ASTM F3044, and ASTM F2129 on EluNIR stents coupled with marketed stainless-steel PMA approved (P020040) NIRFLEX stents to confirm that EluNIR stents possess sufficient Galvanic Corrosion resistance The results met all acceptance criteria and indicate that the stents possess a high resistance to Galvanic Corrosion. | EluNIR Stent; NIRFLEX Stent | Pass  |
|  Stent Weight | 100% in process inspection of stent weight: any stent failing the inspection is rejected. All stents met acceptance criteria. | EluNIR Stent | Pass  |
|  Percent Surface Area | This test determined the percentage of vessel contact stent area to the total area of the vessel. Vessel contact stent area was calculated using measured stent dimensions and divided to theoretical total surface area of vessel at desired diameter for each stent design. The results met acceptance criteria. | EluNIR Stent | Pass  |
|  Dimensional Verification: Stent Inner Diameter (ID) | This test demonstrated that the stent inner diameter is consistent with labeling when deployed at nominal pressure. Each stent was deployed to nominal pressure, and the stent inner diameter was measured at the distal, middle, and proximal sections of the stent. The results indicate that the inner diameter of EluNIR stents is consistent with labeling. | EluNIR Stent | Pass  |
|  Maximum indicated diameter (Largest stent ID of largest labeled diameter) (formally named upper indication diameter) | This test demonstrated that the stent Maximal indicated inner diameter is consistent with labeling when deployed at Maximum labeled pressure. Each stent was deployed to Maximum labeled pressure, and the stent inner diameter was measured at the distal, middle, and proximal sections of the stent. Testing was conducted based on ASTM F2081 and ISO 25539-1. The results indicate that the Maximal indicated inner diameter of EluNIR stents is consistent with labeling. | EluNIR Stent | Pass  |
|  Non-Uniformity of Stent | This test demonstrated stent inner diameter uniformity when deployed at Nominal, Rated Burst, and Maximum pressures. Testing was conducted based on ASTM F2081 and ISO 25539-2. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Stent Foreshortening /Elongation | This test measured the change in stent length from the catheter-loaded (crimped stent) condition to deployment at Nominal, Rated Burst, and Maximum pressures. Testing was conducted based on ASTM F2081 and ISO 25539-2. All results met acceptance criteria. | EluNIR Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Recoil for Balloon Expandable Stents | This test quantified the amount of elastic recoil for the stent after expansion at Nominal and Rated Burst pressures. The system was inflated to either Nominal or Rated Burst pressure and stent diameter was measured at distal, middle and proximal sections of the stent. The system was deflated and the same measurements were performed. The percent recoil is calculated by subtracting the average stent diameter without the balloon from the average stent with the balloon, dividing by the average stent diameter with the balloon and multiplying by 100. Testing was conducted based on ASTM F2079 and ISO 25539-2. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Stent Integrity | This test determined whether deployment of the stent from catheter-loaded (crimped) conditions to either Nominal or Maximum labeled stent diameter can produce mechanical damage to the stent. Each deployed stent was examined under microscope for broken, cracked and/or missed stent struts. All results met acceptance criteria with no visible cracks, breakages or deformations. Testing was conducted based on ISO 25539-2. | EluNIR Stent | Pass  |
|  Radial Stiffness and Radial Strength | This test determined stent resistance to radial compression load. The stents were deployed to nominal stent diameter and placed in radial resistance tester. All results met acceptance criteria. Testing was conducted based on ISO 25539-2. | EluNIR Stent | Pass  |
|  Conformability | This test determined stent flexibility under 2-point bending. The stents were deployed to stent nominal diameter and placed on flexibility tester. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Finite Element Analysis (FEA) – Stress /Strain | This analysis was conducted to ensure that implant conditions to which the stent would be subjected would not result in failure. FEA evaluated the structural integrity of the EluNIR stent when subjected to the expected loading conditions during stent manufacturing, delivery, implantation and clinical loading. Two (2) overlapped stents deployed in a curved vessel were analyzed. The analysis showed that no failure is predicted throughout the stent simulated use. Testing was conducted based on ISO 25539-2 and FDA guidance "Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems" issued on: April 18, 2010, and "Reporting of Computational Modeling Studies in Medical Device Submissions" issued on: September 21, 2016. | EluNIR Bare Metal Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Finite Element Analysis (FEA) – Fatigue | This analysis evaluated the structural integrity of EluNIR stents when subjected to pulsatile loading conditions. Loading during stent manufacturing, delivery and implantation were taken into account. Two overlapped stents deployed in a curved vessel were analyzed. The analysis showed that cyclic pulsatile loading of the EluNIR stent would not result in stent failure due to fatigue. Testing was conducted based on ISO 25539-2 and FDA guidance Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems" issued on: April 18, 2010, and "Reporting of Computational Modeling Studies in Medical Device Submissions" issued on: September 21, 2016. | EluNIR Bare Metal Stent | Pass  |
|  Accelerated Durability Testing (Fatigue) | This test evaluated the durability of EluNIR stents under cyclic loading conditions in an overlapped configuration, on a static bend of 15mm, simulating 10 years of pulsatile fatigue, at physiological conditions. After undergoing tracking and simulated use, the EluNIR stents were deployed into simulated vessel in overlapped configuration and dynamically cycled for 420 million cycles. The test procedure was based on ISO 25539-2. Chronic particulates analysis was performed during accelerated durability testing. Following the accelerated durability testing, the stent appearance was examined microscopically for cracks and/or breakage. Stent chronic coating integrity and corrosion resistance (pitting, crevice, and fretting corrosion resistance) were tested based on ASTM F2129. The EluNIR stent withstood accelerated pulsatile durability under clinically relevant conditions, including bending, overlapping, and pulsatile fatigue without showing signs of mechanical failure, for a lifespan of at least 10 years (as simulated by 420 million cycles). All results of particulate analysis, chronic coating integrity, and corrosion resistance (pitting, crevice and fretting corrosion resistance) met acceptance criteria. | EluNIR Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Magnetic Resonance Imaging (MRI) Safety and Compatibility | This test, performed with single and in combinations of up to three (3) overlapped stents, demonstrated that the EluNIR stent is MR conditional at 1.5-T and 3-T static magnetic field. Maximum temperature rise of 4.5°C; small image artifacts (max. 8mm). Testing was conducted based on ISO 25539-2 and ASTM F2503 and FDA guidance "Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems" Document issued on: April 18, 2010. | EluNIR Stent | Pass  |
|  Radiopacity | This test evaluated the radiopacity of the EluNIR stents prior to deployment and angiographic appearance of the stent post deployment to ensure safe and effective delivery of EluNIR stents to the target vessel location. Testing was conducted based on ISO 25539-2. The EluNIR stent design is based on the PMA approved PIONIR stent (P110004). Radiopacity is not affected by the stent coating; thus the results of the approved products are applicable. | PIONIR Bare Metal Stent | Pass  |
|  Delivery System Dimensional and Functional Attributes  |   |   |   |
|  Dimensional Verification: Delivery System | The following characteristics were tested to conform to the applicable specifications: Distal Tip: total length, Tip Fuse length; Balloon: working length, Outer Diameters (OD), double wall thickness (DTW), Balloon Cones: length; Balloon Shoulder: lengths, OD, Inner Diameters (ID); Radiopaque Marker Bands: Distance between markers, Balloon to marker alignment; Distal Outer Shaft: length; Proximal Shaft: Marker locations (Femoral Marker & Brachial Marker); Delivery System: Total catheter length, Placement; Delivery System Outer Diameters (Distal Shaft OD, Transition Shaft OD, Proximal Shaft OD, Tip Entry OD). | EluNIR Delivery System | Pass  |
|  Delivery, Deployment and Retraction | This test verified the ability of the delivery system to be prepared and tracked through a tortuous simulated use model. The following characteristics were tested: • Guidewire compatibility • Guiding catheter compatibility • Deliverability • Balloon inflation time* • Deployment accuracy (for information only) • Fixation effectiveness (for information only) • Flushing the inner lumen • Maximum deflated balloon outer diameter (for characterization only) This test also measured the retraction forces of the delivery system after deployment of the stent. All results met acceptance criteria. Testing was conducted based on ISO 25539-2 and ASTM F2394. | EluNIR Delivery System | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Balloon Rated Burst Pressure | This test statistically verified with probability/confidence 99.9%/95% that the EluNIR stent system will not rupture below the Rated Burst Pressure. All results met acceptance criteria. Testing was conducted based on ISO 25539-2. | EluNIR Delivery System | Pass  |
|  Balloon Fatigue | This test verified that 90% of balloons withstand a minimum of 10 repeated inflations to Rated Burst Pressure with confidence level of 95%. All results met acceptance criteria. Testing was conducted based on ISO 25539-2. | EluNIR Delivery System | Pass  |
|  Balloon Compliance (Stent diameter vs. balloon pressure) | This test determined variations of inner stent diameter with applied balloon pressure. Testing was conducted based on ASTM F2081 and ISO 25539-1. All results met acceptance criteria. | EluNIR Delivery System | Pass  |
|  Balloon Inflation* and Deflation Time | This test determined the amount of time required to inflate or deflate the delivery catheter balloon. All results met acceptance criteria. Testing was conducted based on ISO 25539-2. | EluNIR Delivery System | Pass  |
|  Catheter Bond Strength | This test determined balloon bond tensile strengths. Hub, body, proximal fuse, and RX-port bonds were measured. All results met acceptance criteria. Testing was conducted based on ISO 10555-1. | EluNIR Delivery System | Pass  |
|  Tip Pull Test | This test determined tensile strength of the system tip. All results met acceptance criteria. Testing was conducted based on ISO 10555-1. | EluNIR Delivery System | Pass  |
|  Flexibility and Kink Test | This test demonstrated the smallest radius that the EluNIR system can conform to prior to kinking. All results met acceptance criteria. Testing was conducted based on ISO 25539-2 and ASTM-F2394. | EluNIR Delivery System | Pass  |
|  Torque Strength | This test demonstrated the number of rotations the catheter can withstand prior to fracture. All results met acceptance criteria. Testing was conducted based on ISO 25539-2. | EluNIR Delivery System | Pass  |
|  Coating Integrity: Hydrophilic Coating | This test demonstrated that hydrophilic coating on the distal shaft and the transition shaft of the EluNIR system does not delaminate from the tube's surface during tracking through simulated use model. All results met acceptance criteria. | EluNIR Delivery System | Pass  |
|  Stent Securement | This test measures the force required to displace a stent in both distal and proximal directions from its original crimped position on the delivery system balloon after the pre-conditioning step when the system was tracked through a simulated use model. All results met acceptance criteria. Testing was conducted based on ISO 25539-2 and ASTM-F2394. | EluNIR Delivery System | Pass  |

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# A2. Coating Characterization Testing

The following methods were developed to characterize and set initial specifications for the EluNIR Ridaforolimus Eluting Coronary Stent System. The coating characterization testing conducted on the device includes those tests summarized in Table 5.

Table 5: Coating characterization testing

|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Coating materials: Polymers (Poly n-Butyl Methacrylate, CarboSil® 20 55D) and Drug Substance (Ridaforolimus) | Raw material lots are not released prior to successfully passing the tests. | EluNIR Stent | Pass  |
|  Coating materials: Polyurethane (Poly n-Butyl Methacrylate, CarboSil® 20 55D) and Drug Substance (Ridaforolimus) | Raw material lots are not released prior to successfully passing the tests. | EluNIR Stent | Pass  |
|  Coating materials: Polyurethane (Poly n-Butyl Methacrylate, CarboSil® 20 55D) and Drug Substance (Ridaforolimus) | Raw material lots are not released prior to successfully passing the tests. | EluNIR Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Appearance of Stent | This test verified that the EluNIR stent mounted on the catheter has a metallic appearance, with a transparent coating of smooth texture. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Coating Adhesion | This test characterized the adhesion of stent coating to metal strut. No coating delamination was detected after EluNIR system tracking through a simulated use model and deployment to maximal labeled diameter. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Acute Stent Coating Integrity | This test determined coating integrity in the following configurations: • At baseline – without expansion and after expansion to stent nominal and over-expansion diameter • After tracking through a simulated use model and deployment to maximal labeled diameter Stent coating was examined using light and scanning electron microscopes; all detected coating imperfections were recorded and measured. Any compromised coating area was calculated as a percentage of entire coated stent surface. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Chronic Coating Integrity (after durability test) | This test determined the coating integrity of the EluNIR stent after the accelerated durability test: 420 million cycles of radial pulsated loading in an overlapped configuration on a static bend of 15mm, simulating 10 years of pulsatile fatigue at physiological conditions. Light and scanning electron microscopes were used. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Coating Thickness | This test determined coating thickness measured on the stent cross sections prepared from the distal, middle, and proximal stent areas. Coating thickness was demonstrated to be uniform and consistent along the stent's length, as well as on different stent surfaces (inner, outer, side surfaces). For characterization only. | EluNIR Stent | Pass  |
|  Coating Uniformity Along Stent Length (formally named Drug Coating Uniformity along Stent Length) | This test evaluated coating uniformity by measuring the coated drug at various locations of the stent. Longitudinal and circumferential coating uniformity were tested using separate stents of the same size. Multiple stent segments were cut in longitudinal and circumferential stent directions, and drug amount was determined for each segment. Variations of drug content in each segment were calculated as a percentage of nominal fractional drug amounts for segments. Uniformity of drug distribution along the stent length and in circumferential directions was demonstrated. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Acute Particulates Analysis (at baseline and over-expansion in beaker) (formally named Particulate matter – baseline acute stent particulate analysis) | This test evaluated the particulate matter generated during deployment and over-expansion of the EluNIR stent in a beaker of water. The distal end (balloon and stent) was inserted into glassware filled with clean water and the stent was deployed to nominal and then to maximum labeled diameter. After agitation, aliquots of the water were withdrawn and the particle quantities and sizes were counted and recorded. The results of the particulate testing and coating integrity are for characterization. All results met acceptance criteria | EluNIR Stent | Pass  |

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|  Test | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Acute Particulates Analysis (after simulated use) (formally named Particulate matter: over- expansion after simulated use in overlapped conditions) | This test determined particulate matter after navigation through a simulated use model and following deployment to Rated Burst Pressure inside simulated vasculature. A second stent was then tracked and deployed over the first in an overlapping configuration. Water was drawn through the vasculature and the particle quantities and sizes were counted and recorded. The results of the particulate testing and coating integrity are for characterization. All results met acceptance criteria | EluNIR Stent | Pass  |
|  Chronic Particulates Analysis (during accelerated durability test) | This test determined particulate matter after the accelerated durability test: 420 million cycles of radial pulsated loading in an overlapped configuration on a static bend of 15mm, simulating 10 years of pulsatile fatigue at physiological conditions. Particle quantities and sizes were counted and recorded for each pair of stents. The results of particulate testing and coating integrity are for characterization. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Particulate Matter (formally named Particulate matter - chemical characterization: Acute and Chronic) | This test characterized and identified particulates collected from EluNIR stents that had been tracked through a simulated use model and deployed to maximum labeled diameter in an overlapped configuration. Particulates that had been collected from EluNIR stents during accelerated durability testing also were analyzed for chemical identification. | EluNIR Stent | Pass  |
|  Assay (Drug Content) (formally named Drug Assay) | An assay test was conducted to quantitatively verify the total amount of drug on the EluNIR stent. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Drug Identification | All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Uniformity of Dosage Units (formally named Drug content uniformity) | This test verified uniformity of the drug content between individual stents. Multiple stents were tested for verification. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Degradation Products/Drug Impurities (formally named Drug Impurities and degradation products) | This test quantitatively verified the amount and type of degradation products. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Drug Elution | This in vitro test determined the drug release profile of the drug substance. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Antioxidant Preservative-Butylated Hydroxy Toluene (BHT) | This test determined the amount of BHT in the EluNIR stent. All results met acceptance criteria. | EluNIR Stent | Pass  |
|  Residual Solvents - Tetrahydrofuran (THF) | This test determined the amount of residual solvent in the EluNIR stent. All results met acceptance criteria. | EluNIR Stent | Pass  |

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# A3. Chemistry Manufacturing and Controls (CMC) Testing

Where applicable, International Conference on Harmonization (ICH) guidelines were followed for the testing routinely performed on EluNIR stents as part of CMC. This testing is summarized in Table 6. Information to support the stability of the EluNIR stent is summarized separately in Section IX A4.

Table 6: Stent release test

|  Test | Test Description | Test Article  |
| --- | --- | --- |
|  Appearance of Stent | A visual inspection is conducted to verify that the EluNIR stent meets the product's appearance specifications. | EluNIR Stent  |
|  Drug Identity | Assay is conducted to verify the identity of the drug substance, ridaforolimus, on the EluNIR Stent. | EluNIR Stent  |
|  Drug Content | Assay is conducted to quantitatively verify that the total amount of drug on the EluNIR stent met specifications for finished goods release. | EluNIR Stent  |
|  Uniformity of Dosage Units | Multiple stents are tested to verify that the uniformity of the drug content between individual stents was within specifications established for finished goods release. | EluNIR Stent  |
|  Degradation Products / Drug Impurities | HPLC analysis is conducted to quantitatively verify the amount and type of degradation products on the EluNIR Stent. | EluNIR Stent  |
|  Drug Elution | The in vitro release profile for ridaforolimus is measured on the EluNIR stent. Specifications are based on the elution characteristics of clinical and stability data. The product meets specifications established for finished goods release. | EluNIR Stent  |
|  Particulate Matter | Particulate levels are monitored to verify that they remain below acceptable levels as established in the product's specifications. | EluNIR Integrated Stent System (Stent mounted on Delivery System)  |
|  Residual Solvent* | The amount of Tetrahydrofuran (THF) on the EluNIR stent is determined to verify that the residual level of the solvent used in the manufacturing process is within the specification limits established for finished goods release. | EluNIR Stent  |
|  Antioxidant Preservative* | The levels of Butylated Hydroxy Toluene (BHT) on the EluNIR stent is quantified to verify that it is within the specification limits established for finished goods release. | EluNIR Stent  |
|  Bacterial Endotoxins Test | The amount of bacterial endotoxins is verified to be within the specification limits established for finished goods release. | EluNIR Integrated Stent System (Stent mounted on Delivery System)  |
|  Sterility Biological Indicator | The release of each lot of EluNIR Stent System is based on verification that the sterilization load complies with validated sterilization cycle parameters and satisfies the requirement for labeling the finished goods as sterile. | EluNIR Integrated Stent System (Stent mounted on Delivery System)  |

*Not a release test

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## A4. Stability/Shelf Life

A formal stability study was conducted to establish a shelf life expiration date for the EluNIR Stent System. Testing included appearance of stent, drug assay, degradation products / drug impurities, drug elution, particulate matter, antioxidant preservative (BHT), product sterility and packaging integrity (visual inspection, tensile strength [peel test], seal integrity [bubble leak test], dye penetration and bacterial endotoxin).

Testing to establish container closure integrity was conducted to ensure sterility was maintained during the shelf life of the product. Functional testing of the stent system was conducted on aged products. The data generated to date support a shelf life of 24 months.

## A5. Sterilization

The EluNIR Stent System is sterilized using ethylene oxide (EO) sterilization. The cycle is validated per ISO 11135 “Medical Devices-Validation and Routine Control of Ethylene Oxide Sterilization”. Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$ and the requirements of ISO 10993-7 “Ethylene Oxide Sterilization Residuals”. In addition, the amount of bacterial endotoxins was verified to be within the specification limits.

## B. Animal Studies

### B1. Major Supportive Animal Studies

Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials. Consequently, a series of animal studies were conducted to evaluate safety, efficacy (proof of concept dosing), and overall product performance.

All animal studies (feasibility, safety, pharmacokinetic and acute) were conducted in accordance with §21CFR 58 (Good Laboratory Practices). The results of these studies support the safety and biocompatibility of the EluNIR Ridaforolimus Eluting Coronary Stent System. Table 7 includes summaries of the major animal studies performed to support product safety.

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Table 7: Summary of major supportive animal studies

|  Study Number | Stent Design | Type/Number of Animals | Number of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- |
|  UWS00025
180-day Safety Study, Overlapping Configuration | Test Article: EluNIR Ridaforolimus Eluting Coronary Stent System (DES), 2.75/3.0 x 12mm
Control Article: Presillion Plus (BMS) 2.75/3.0 x 12mm
GLP: Yes | Yucatan mini swine/28 (11 Male [castrated] and 17 Female [nulliparous]) | Test: 74 (37 pairs)
Control: 72 (36 pairs)
(LCX, LAD, and/or RCA)
Animals received at least one overlapping pair of test stents/SDSs and one overlapping pair of control stents/SDSs in separate vessels.
2 stents/vessel (overlapping)
2-3 overlapping stent pairs/animal (4 to 6 stents/animal) | Up to 180 days (Days 3, 30 and 180) | 1. Device Deployment and Acute Performance
2. Thromboresistance Assessment
3. Activated Clotting Times
4. Quantitative Coronary Angiography
5. Animal Observations
5.1 Mortality/Moribundity
5.2 Clinical Observations
5.3 Body Weights and Body Condition Score
6. Clinical Pathology
6.1 Hematology
6.2 Fibrinogen
6.3 Serum Chemistry
7. Anatomic Pathology
7.1 SEM Analysis
7.2 Histomorphometry
7.3 Histopathology  |
|  UWS00024
360-day Safety Study, Single Configuration | Test Article: EluNIR Ridaforolimus Eluting Coronary Stent System, multiple doses (DES) 2.75/3.0 x 17mm 2.75/3.0 x 33mm
Control Article: Presillion Plus (BMS) 2.75/3.0 x 17mm
GLP: Yes | Yucatan mini swine/62 (47 Male [castrated] and 15 Female [nulliparous])
Note: 2 males were early dead on Day 0; did not reach protocol time point. | Test: 87 (DES=55 [excluding 2 early dead], High dose DES (5x drug load, 2x polymer load)=16, Long stent DES=16 [excluding 1 early dead])
Control: 51 [excluding 1 early dead]
(LCX, LAD, RCA)
Animals received both test and control (up to 3 stents (DES, BMS, long DES, or high dose DES)).
1 stent/vessel
2 to 3 stents/animal | Up to 360 days (Days 3, 30, 90, 180, and 360) | 1. Device Deployment and Acute Performance
2. Thromboresistance Assessment
3. Activated Clotting Times
4. Quantitative Coronary Angiography
5. Animal Observations
5.1 Mortality/Moribundity
5.2 Clinical Observations
5.3 Body Weights and Body Condition Score
6. Clinical Pathology
6.1 Hematology
6.2 Fibrinogen
6.3 Serum Chemistry
7. Anatomic Pathology
7.1 SEM Analysis
7.2 Histomorphometry
7.3 Histopathology  |

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|  Study Number | Stent Design | Type/Number of Animals | Number of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- |
|  UWS00033, Acute Performance Study, Stent Delivery System (SDS) | Test Article: EluNIR Ridaforolimus Eluting Coronary Stent System, multiple doses (Modified Process-DES, 3.0 x 17 mm)
Control:
• EluNIR Ridaforolimus Eluting Coronary Stent System (DES, 3.0 x 17mm)
• Resolute Integrity Stent Systems (DES, 3.0 x 18mm)
GLP: Yes | Yorkshire swine/2 (Male [castrated]) | Test: 12 (EluNIR Modified SDS)
Control: 24 (EluNIR SDS=12; Resolute SDS=12) (LCX, LAD, RCA)
Animals received both test and control.
6 stents (n=2/type)/vessel tracked including 2 deployed 18 stent/animal | Acute | 1. Device Deployment and Acute Performance
2. Activated Clotting Times
3. Quantitative Coronary Angiography
4. Animal Observations
4.1 Mortality/Moribundity  |

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|  Study Number | Stent Design |   | Type/ Number of Animals | Number of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- | --- |
|  UWS00035 Acute Performance Study, Stent Delivery System (SDS) | Test Article: |   | Yorkshire swine/5 (Male) | Test: 12 (Improved BioNIR 2.5x8mm); 12 (Improved BioNIR 4.0x33mm); 12 (BioNIR 2.75x44mm); 12 (BioNIR 4.0x44mm); 12 (Improved NIRxcell 2.5x8mm); 12 (Improved NIRxcell 4.0x33mm) Control: 12 (Control BioNIR 2.5x8 mm); 12 (Control BioNIR 4.0x33mm); 12 (Control NIRxcell 2.5x8mm); 12 (Control NIRxcell 4.0x33mm) (RCA, LAD, LCX and/or and branches thereof). BioNIR test articles (2.75x44mm and 4.0x44mm) will be tracked through a coronary artery and two will be implanted in a vessel of appropriate length and diameter (e.g., mammary artery, subclavian artery, etc.) Animals received both test and control. Up to 8 stents tracked and 2 stents implanted/vessel tracked up to 20 stents/animal | Acute | 1. Device Deployment and Acute Performance
2. Activated Clotting Times
3. Quantitative Coronary Angiography
4. Animal Observations
4.1 Mortality/Moribundity
4.2 Clinical Observations
4.3 Body Weights and Body Condition Score  |
|   |  Identification and Description | Size  |   |   |   |   |
|   |  Modified EluNIR; Smallest/ shortest (DES) | 2.5x8mm  |   |   |   |   |
|   |  Modified EluNIR; Largest/ longest (DES) | 4.0x33mm  |   |   |   |   |
|   |  Modified EluNIR; Smallest long (DES) | 2.75x44mm  |   |   |   |   |
|   |  Modified EluNIR; Largest long (DES) | 4.0x44mm  |   |   |   |   |
|   |  Modified NIRxcell; Smallest/shortest (BMS) | 2.5x8mm  |   |   |   |   |
|   |  Modified NIRxcell; Largest/ longest (BMS) | 4.0x33mm  |   |   |   |   |
|   |  Control Article:  |   |   |   |   |   |
|   |  Identification and Description | Size  |   |   |   |   |
|   |  Control EluNIR; Smallest/shortest (DES) | 2.5x8mm  |   |   |   |   |
|   |  Control EluNIR; Largest/ longest (DES) | 4.0x33mm  |   |   |   |   |
|   |  Control NIRxcell; Smallest/shortest (BMS) | 2.5x8mm  |   |   |   |   |
|   |  Control NIRxcell; Largest/ longest (BMS) | 4.0x33mm  |   |   |   |   |
|  GLP: Yes  |   |   |   |   |   |   |

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|  Study Number | Stent Design | Type/ Number of Animals | Number of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- |
|  UWS00020 Local/Systemic pharmacokinetics (PK) Study | Test Article: EluNIR Ridaforolimus Eluting Coronary Stent System (DES), 2.75/3.0 x 17mm
Control Article: N/a
GLP: Yes | Yucatan mini swine/27 (10 Male [castrated] and 1 Female [nulliparous]) | Test: 73
Control: N/a (RCA, LAD, LCX and/or branches thereof). 1 stent/vessel
2 to 3 stents/animal | Up to 456. (Days 1, 3, 7, 14, 30, 60, 90, 180, and 456) | 1. Device Deployment
2. Activated Clotting Times
3. Quantitative Coronary Angiography
4. Animal Observations
4.1 Mortality/Moribundity
4.2 Clinical Observations
4.3 Body Weights and Body Condition Score
5. Clinical Pathology
5.1 Hematology
5.2 Fibrinogen
5.3 Serum Chemistry
6. Ridaforolimus Extraction and Bioanalysis
6.1 Systemic Drug Levels
6.2 Drug Release Profile (Stent Drug Levels)
6.3 Arterial Tissue Drug Levels
6.4 Myocardial Tissue Levels
7. Anatomic Pathology
7.1 Gross Necropsy  |

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B2. Biocompatibility Studies

A series of GLP biocompatibility tests and USP Physicochemical tests were conducted to demonstrate that the components of the EluNIR Ridaforolimus Eluting Coronary Stent System are non-toxic and biocompatible. Tests were conducted on final, ethylene oxide-sterilized EluNIR coated stents, polymer-only coated stents, stent delivery systems (delivery system and modified delivery system), stent protector sleeve and the flushing tool. These test articles were processed in the same manner as the finished EluNIR product. In all of these test systems, the materials were non-reactive and met all acceptance criteria. The results of the biocompatibility studies indicated that the EluNIR Coronary Stent System was biologically safe and acceptable for clinical use:

- The EluNIR Stent was categorized as an implant device with permanent contact duration with circulating blood (>30 days).
- The Delivery System was categorized as an externally communicating device with limited contact duration with circulating blood (<24 hours).
- The Packing System was categorized as follows:
- The Stent Protector Sleeve (sleeve segment), the primary immediate packaging component which directly interacts with the coating formulation, is a non-contact device that does not contact the patient's body directly or indirectly
- The Flushing Tool, the associated component included in the Coronary Hoop packaging component, does not come in direct contact with the patient's body; however, since there is indirect blood path contact, it is considered to be an externally communicating device with limited (< 24 hours), indirect contact with blood.

All biocompatibility testing was conducted in accordance with one or more of the following general regulations, standards and guidance documents:

- Good Laboratory Practices Regulations (21 CFR § 58)
- Guidance for Industry: "Coronary Drug-Eluting Stents-Nonclinical and Clinical Studies" (March 2008)
- Guidance for Industry and FDA Staff: "Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems"
- Blue Book Memorandum #G95-1 "Use of International Standard ISO-10993, 'Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,'" (May 1, 1995)
- ISO 10993-1, "Biological Evaluation of Medical Devices: Evaluation and Testing within a Risk Management Process"
- ISO 14971, Medical devices: "Application of Risk Management to Medical Devices"
- USP "Physicochemical Test – Containers Plastics" <661>
- FDA Guidance for Industry: "Container Closure Systems for Packaging Human Drugs and Biologics"

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Table 8 provides a summary of the biocompatibility testing conducted to support the EluNIR Ridaforolimus Eluting Coronary Stent System.

Table 8: Summary of biocompatibility testing

|  Test Name | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|  Cytotoxicity | ISO 10993-5: In Vitro Cytotoxicity (L929 MEM Elution) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Delivery system | Pass (non-cytotoxic)  |
|   |  MHLW, PFSB/ELD (Iyakushin) Notification No.0213001 (Colony Forming Cell Assay with V79 Chinese hamster lung cells) | • Modified delivery system • Stent Protector Sleeve (sleeve segment) • Flushing tool | Pass (non- cytotoxic)  |
|  Pyrogenicity | ISO-10993-11: Systemic Toxicity (Material Mediated Rabbit, Injection) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Delivery system • Modified delivery system | Pass (non- pyrogenic)  |
|   |  USP, General Chapter <151>, Pyrogen Test  |   |   |
|  Sensitization | ISO-10993-10: Sensitization (Guinea pig Maximization) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Delivery system • Modified delivery system • Flushing tool | Pass (non-sensitizing)  |
|  Acute Intracutaneous Reactivity | ISO-10993-10: Irritation (Injection) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Delivery system • Modified delivery system • Flushing tool | Pass (non-irritant)  |
|  Acute Systemic Toxicity | ISO-10993-11: Systemic toxicity (Acute, Intravenous) | • Coated (drug and polymer blend) stent • Polymer only coated stent • Delivery system • Modified delivery system • Flushing tool | Pass (non-toxic)  |
|   |  ISO-10993-11: Systemic toxicity (Acute, Subcutaneous) | • Coated (drug and polymer blend) stent • Polymer only coated stent | Pass (non-toxic)  |
|  Hemocompatibility /Hemolysis | ISO-10993-4: In Vivo Thromboresistance (see Section XI B2) | • Stent System | Pass (non-thrombogenic)  |
|   |  ISO-10993-4: In Vitro ASTM F756: Hemolytic Properties of Materials | • Coated (drug and polymer blend) stent | Pass (non-thrombogenic)  |

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|  Test Name | Test Description | Test Article | Results  |
| --- | --- | --- | --- |
|   |  | • Modified delivery system
• Stent Protector Sleeve (sleeve segment)
• Flushing tool | Pass
(non-thrombogenic)  |
|  Complement Activation | IS0-10993-4: Complement Activation Test (C3a and SC5b-9) | • Coated (drug and polymer blend) stent
• Polymer only coated stent
• Delivery system
• Modified delivery system | Pass  |
|  Implantation | IS0-10993-6: Local Effects After Implantation (6 weeks, Rabbit, Intramuscular) | • Coated (drug and polymer blend) stent
• Polymer only coated stent | Pass  |
|   |  IS0-10993-6: Local Effects After Implantation (12 weeks, Rabbit, Intramuscular) | • Coated (drug and polymer blend) stent
• Polymer only coated stent | Pass  |
|  Mutagenesis | IS0-10993-3: Bacterial Reverse Mutation Assay (Ames test) | • Coated (drug and polymer blend) stent
• Polymer only coated stent
• Delivery system | Pass
(non-mutagenic)  |
|   |  IS0-10993-3: Lymphoma Assay for Mammalian Cell Mutagenicity | • Coated (drug and polymer blend) stent
• Polymer only coated stent | Pass
(non-mutagenic)  |
|   |  ASTM E1280-1997 Standard Guide for Performing the Mouse Lymphoma Assay for Mammalian Cell Mutagenicity  |   |   |
|   |  OECD Guidelines for the Testing of Chemicals, Section 4, Test No. 476: In vitro Mammalian Cell Gene Mutation Test  |   |   |
|   |  IS0-10993-3: Mouse Peripheral Blood Micronucleus Study | • Coated (drug and polymer blend) stent
• Polymer only coated stent | Pass
(non-mutagenic)  |
|   |  OECD Guidelines for the Testing of Chemicals, Section 4, Test No. 474: Mammalian Erythrocyte Micronucleus Test  |   |   |
|  Material Characterization (USP Physicochemical Testing) | USP Physicochemical Extracts <661> (Aqueous) | • Coated (drug and polymer blend) stent
• Delivery system
• Stent Protector Sleeve (sleeve segment) | Pass  |

In vivo animal testing conducted on the EluNIR Stent System evaluated the effects of drug multiple doses and device exposure in a porcine coronary artery for up to 360 days, in lieu of IS0-10993 chronic toxicity and muscle implantation testing. These

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studies showed no evidence of local arterial or systemic toxicity. The resulting tissue histology in these studies did not display pathology consistent with drug or polymer-induced toxicity. The animal studies are summarized separately in Section XI B1.

Formal carcinogenicity testing was not conducted on the EluNIR Stent. The carcinogenic potential of the EluNIR stent is minimal based on the limited period of ridaforolimus release, on the types and quantities of materials present, and on the favorable outcomes and results of the mutagenesis testing (see Table 8).

Formal reproductive toxicity testing was not conducted on the EluNIR Stent. The reproductive potential of the EluNIR stent is minimal based on the limited period of ridaforolimus release, on the types and quantities of materials present.

Based on in vitro analytical and stability testing results, there is no evidence to suggest that, under established processing and storage conditions, any chemical interactions occur between the polymers (CarboSil® 20 55D and PBMA) and the ridaforolimus drug that would lead to the formation of covalent bonds or that would alter the structure of the drug in any way to form a new intermediate or molecular entity.

## C. Additional Studies

### C1. Studies on the Drug Substance - Drug Interactions

Several drugs are known to affect ridaforolimus metabolism, and other drug interactions may also occur. Ridaforolimus is known to be a substrate for both cytochrome P4503A4 (CYP3A4) and P-glycoprotein (PgP). Ridaforolimus absorption and subsequent elimination may be influenced by drugs that affect these pathways.

Formal drug interaction studies have not been performed with the EluNIR stent because of limited systemic exposure to ridaforolimus eluted from EluNIR stent. Therefore, due consideration should be given to the potential for both systemic and local drug interactions in the vessel wall, when deciding to place the EluNIR stent in a patient taking a drug with known interaction with ridaforolimus, or when deciding to initiate therapy with such a drug in a patient who has recently received a EluNIR stent.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The principal safety and effectiveness and pharmacokinetics information for the EluNIR™ Ridaforolimus Eluting Coronary Stent System (EluNIR) were derived from a pivotal clinical trial as well as PK trial, both under IDE# G140107:

- The BIONICS clinical trial CIP#BioNIR-001
- The BIONICS-PK clinical trial CIP# BioNIR-PK-001

A summary of the two (2) clinical studies is presented below.

### 1) BIONICS CLINICAL TRIAL (CIP#: BioNIR-001)

The BIONICS trial evaluated the safety and efficacy of EluNIR Ridaforolimus in comparison to the Medtronic Zotarolimus-Eluting Resolute Stent, for its indication for use of improving coronary luminal diameter in patients with symptomatic heart disease due to de novo lesions ≤30mm in length in native coronary arteries with reference

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diameters of 2.5mm to 4.25mm. The trial has reached the primary endpoint. Patient follow-up is ongoing up to five years, per protocol.

## A. Study Design:

BIONICS is a prospective, multi-center, single-blind, two-arm, 1:1 randomized clinical trial with 1919 enrolled patients with a wide spectrum of Percutaneous Coronary Intervention (PCI) indications (stable angina as well as ACS, including subacute ST-Elevated Myocardial Infarction (STEMI) (&gt;24 hours since first hospital presentation)), "more comers" concept. It is being performed at 76 sites in the US, Canada, Europe and Israel. Enrollment in the study started on March 12, 2014 and was completed on August 28, 2015.

The study objective was to demonstrate clinical and angiographic non-inferiority for the EluNIR in comparison to the Resolute Zotarolimus-Eluting Stent System.

The primary clinical endpoint was target lesion failure (TLF) at one year, with an additional angiographic endpoint of in-stent late lumen loss evaluated in a sub-set of 202 (158 evaluable) patients at 13 months. Among the patients of this subset, 155 were also evaluated by intravascular ultrasound (IVUS) at baseline and at the 13-month follow-up (111 evaluable at 13-months follow-up).

From recent US trials of best in class DES (Xience V, Promus Element and Resolute), the 1-year TLF rate in patients with non-complex lesions not undergoing routine angiographic follow-up was approximately 4.1%. Using the assumption of the more-comers' design, the 1-year event rate was conservatively increased by ~40% (assuming enrollment rate for complex patients/lesions is 40% with double the standard event rate) – thus 5.8%. Therefore, with a one-sided 95% upper bound of the confidence interval of 3.3% (a relative 57% margin) and 1:1 randomization, enrolling 1810 patients (905 per group) provided 90% power to demonstrate non-inferiority. Assuming 95% follow-up rate at 1 year, approximately 1906 patients were enrolled (953 in each group).

Randomization was stratified by the presence of medically treated diabetes vs. no medically treated diabetes, acute coronary syndrome (ACS, unstable angina, non-STEMI and subacute STEMI) vs. no ACS (i.e., stable coronary artery disease), and by site. The primary analysis of the BIONICS data was performed on the Full Analysis Set (FAS) which was defined as all randomized subjects assigned to treatment per randomization, regardless of whether they received the study stent. Subjects were included in the FAS once the study stent has been advanced beyond the guide catheter (de-registered subjects are excluded).

A dedicated medical monitor (blinded to treatment assignment) reviewed the safety data on an ongoing basis. An independent Clinical Events Committee (CEC) adjudicates all potential clinically significant and relevant cardiac events data. The trial was supervised by an independent Data Safety Monitoring Board (DSMB).

Angiographic, IVUS and ECG Core laboratories enabled standardized and objective analysis of the data.

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Patients' follow-up is described in the following timelines, per protocol: 30 days, 6 months, 1 year post randomization, and annually thereafter up to 5 years.

The schematic diagram for the study design is displayed in Figure 4.

![img-3.jpeg](img-3.jpeg)
Figure 4: BIONICS Clinical Trial Design

# A1. Clinical Inclusion and Exclusion Criteria

# Inclusion Criteria

All inclusion criteria must have been present for the patient to be eligible for enrollment.

# General Inclusion Criteria:

1. Age  $\geq 18$  years.
2. An indication for percutaneous coronary intervention (PCI) including angina (stable or unstable), silent ischemia (in absence of symptoms a visually estimated target lesion diameter stenosis (DS) of  $\geq 70\%$ , a positive non-invasive stress test, or fractional flow reserve (FFR)  $\leq 0.80$  must be present), non-ST-elevation myocardial infarction (NSTEMI), or recent ST-elevation myocardial infarction (STEMI). For STEMI the time of presentation to the first treating hospital, whether a transfer facility or the study hospital, must have been  $&gt;24$  hours prior to randomization with enzyme levels (creatine kinase-muscle-brain isoenzyme [CK-MB] or Troponin) demonstrating that either or both enzyme levels have peaked.
3. Non-target vessel PCI were allowed prior to randomization depending on the time interval and conditions:

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a. During Baseline Procedure:

- PCI of non-target vessels performed during the baseline procedure itself immediately prior to randomization if successful and uncomplicated defined as: &lt;50% visually estimated residual DS, Thrombolysis in Myocardial Infarction (TIMI) Grade 3 flow, no dissection ≥ type C (National Heart, Lung, and Blood Institute [NHLBI] [coronary artery dissection scale]), no perforation, no persistent ST segment changes, no prolonged chest pain, no TIMI major or Bleeding Academic Research Consortium (ARC) type 3 bleeding.

b. Less than 24 hours prior to Baseline Procedure: Not allowed (see Criteria#2).

c. 24 hours-30 days prior to Baseline Procedure:

i. PCI of non-target vessels 24 hours to 30 days prior to randomization if successful and uncomplicated as defined above.

ii. In addition, in cases where non-target lesion PCI had occurred 24-72 hours prior to the baseline procedure, at least two sets of cardiac biomarkers were drawn at least 6 and 12 hours after the non-target vessel PCI.

iii. If cardiac biomarkers were initially elevated above the local laboratory upper limit of normal (ULN), serial measurements must have demonstrated biomarkers were falling.

d. Over 30 days prior to Baseline Procedure:

i. PCI of non-target vessels performed greater than 30 days prior to procedure whether or not successful and uncomplicated.

4. Subject or legal guardian was willing and able to provide informed written consent and comply with follow- up visits and testing schedule.

## Angiographic Inclusion Criteria (visual estimate):

1. Target lesion(s) were located in a native coronary artery or bypass graft conduit with visually estimated diameter of ≥2.5 mm to ≤4.25 mm.

2. Complex lesions were allowed including calcified lesions (lesion preparation with scoring/cutting and rotational atherectomy were allowed), presence of thrombus that was non-occlusive and did not require thrombectomy, chronic total occlusion (CTO), bifurcation lesions (except planned dual stent implantation), ostial right coronary artery (RCA) lesions, tortuous lesions, bare metal stent (BMS) restenotic lesions, protected left main lesions, and saphenous vein graft (SVG) lesions.

3. Overlapping stents were allowed.

## Exclusion Criteria

All exclusion criteria must have been absent for the patient to be eligible for enrollment.

## General Exclusion Criteria:

1. STEMI within 24 hours of initial time of presentation to the first treating hospital, whether at a transfer facility or the study hospital, or in whom enzyme levels (either CK-MB or Troponin) had not peaked.

2. PCI within the 24 hours preceding the baseline procedure.

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3. Non-target lesion PCI in the target vessel within 12 months of the baseline procedure.
4. History of stent thrombosis (ST).
5. Cardiogenic shock (defined as persistent hypotension [systolic blood pressure &lt;90 millimeters of mercury (mmHg) for more than 30 minutes]) or requiring pressors or hemodynamic support, including intra-aortic balloon pump.
6. Subject was intubated.
7. Known left ventricular ejection fraction (LVEF) &lt;30%.
8. Relative or absolute contraindication to dual antiplatelet therapy (DAPT) for 12 months (including planned surgeries that could not be delayed)
9. Subject had an indication for chronic oral anticoagulant treatment (with either vitamin K antagonists or novel oral anticoagulants)
10. Calculated creatinine clearance &lt;30 milliliters (mL)/minute (min) using Cockcroft-Gault equation (&lt;40 mL/min for subjects participating in the angiographic follow-up sub-study).
11. Hemoglobin &lt;10 grams (g)/deciliter (dL).
12. Platelet count &lt; 100,000 cells/cubic millimeter (mm3) or &gt;700,000 cells/mm3.
13. White blood cell (WBC) count &lt;3,000 cells/mm3.
14. Clinically significant liver disease.
15. Active peptic ulcer or active bleeding from any site.
16. Bleeding from any site within the prior 8 weeks requiring active medical or surgical attention.
17. If femoral access was planned, significant peripheral arterial disease which precluded safe insertion of a 6F sheath.
18. History of bleeding diathesis or coagulopathy or refusal of blood transfusions.
19. Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months prior to screening, or any permanent neurologic defect attributed to a CVA.
20. Known allergy to the study stent components, whether in the EluNIR or Resolute, e.g., cobalt, nickel, chromium, molybdenum, CarboSil®, poly-n-butylmethacrylate (PBMA), BioLinx polymer, or limus drugs (ridaforolimus, zotarolimus, tacrolimus, sirolimus, everolimus, or similar drugs or any other analogue or derivative or similar compounds).
21. Known allergy to protocol-required concomitant medications such as aspirin, or DAPT (clopidogrel, prasugrel, ticagrelor), or heparin and bivalirudin, or iodinated contrast that cannot be adequately pre- medicated.
22. Any co-morbid condition that may have caused non-compliance with the protocol (e.g., dementia, substance abuse) or reduced life expectancy to &lt;24 months (e.g., cancer, severe heart failure, severe lung disease).
23. Subject was participating in or planned to participate in any other investigational drug or device clinical trial that had not reached its primary endpoint.
24. Women who were pregnant or breastfeeding (women of child-bearing potential

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[WOCBP] must have had a negative pregnancy test within 1 week before treatment).

25. Women who intended to become pregnant within 12 months after the baseline procedure (WOCBP who were sexually active must have agreed to use a reliable method of contraception from the time of screening through 12 months after the baseline procedure).

26. Subject had received an organ transplant or was on a waiting list for an organ transplant.

27. Subject was receiving or scheduled to receive chemotherapy within 30 days before or any time after the baseline procedure.

28. Subject was receiving oral or intravenous (IV) immunosuppressive therapy or had known life-limiting immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus [HIV]). Corticosteroids were allowed.

## Angiographic Exclusion Criteria (visual estimate):

1. Target lesions in more than two major coronary arteries (i.e., 2 of left anterior descending [LAD], left circumflex [LCX], right coronary artery [RCA]) and their respective branches (the Ramus Intermedius was defined as a branch of the LCX).

2. More than two target lesions per target vessel were planned (two lesions separated by less than 10 mm that could have been covered by a single stent were considered one lesion).

3. More than 100 mm length of planned study stenting in the entire coronary tree.

4. Occlusive thrombus and/or a thrombus that required thrombectomy in a target vessel.

5. Unprotected left main lesions; ≥30%, or planned unprotected left main intervention.

6. Ostial LAD or LCX lesions (stenting of any diseased segment within 5 mm of the unprotected left main coronary artery).

7. Bifurcation lesions with planned dual stent implantation.

8. Stenting of lesions due to drug-eluting stent (DES) restenosis.

9. Another lesion in a target or non-target vessel (including all side branches) was present that required or had a high probability of requiring PCI within 21 months after the baseline procedure.

## A2. Follow-up Schedule

Clinical follow-up was performed at 30 days, 6 months, and 1 Year. The next follow up visits will take place at 2, 3, 4, and 5 years post randomization.

The trial also included an angiographic sub-study, with 202 consenting subjects (158 evaluable) at participating North American sites undergoing planned angiographic follow-up at 13 months after enrollment, and the first 155 of these subjects also undergoing intravascular ultrasound (IVUS) at baseline and at 13 months following randomization (111 evaluable at 13 months follow up).

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A3. Clinical Endpoints

1. Primary Endpoint:
Target Lesion Failure (TLF) at 12 months defined as the composite of cardiac death, target vessel-related myocardial infarction (MI)¹, or ischemia-driven target lesion revascularization (TLR).

2. Clinical Secondary Endpoint
Secondary endpoints were evaluated at 30 days, 6 months, and 1 year for this analysis, with 2, 3, 4, and 5-year analyses ongoing (except as noted):
- Device, Lesion, and Procedure Success at time of baseline procedure
- TLF at 30 days, 6 months, and 2, 3, 4, and 5 years
- Major adverse cardiac events (MACE; the composite rate of cardiac death, any MI, or ischemia-driven TLR)
- Target vessel failure (TVF; the composite rate of death, target vessel related MI, or ischemia-driven target vessel revascularization [TVR])
- All-cause mortality
- Cardiac death
- MI
- Target vessel related MI
- Ischemia-driven TLR
- Ischemia-driven TVR
- Stent thrombosis (ARC definite and probable)

3. Other Secondary Endpoints
Angiographic Sub-Study
- Angiographic in-stent loss (LL)
IVUS Sub-Study
- In-stent percent neointimal hyperplasia (NIH)
- Stent malapposition

¹ Periprocedural MIs are included per SCAI definitions as follows:
- In patients with normal baseline CK-MB: The peak CK-MB measured within 48 hours of the procedure rises to ≥10x the local laboratory ULN, or to ≥5x ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent LBBB, OR in the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured within 48 hours of the PCI rises to ≥70x the local laboratory ULN, or ≥35x ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent LBBB.
- In patients with elevated baseline CK-MB (or cTn) in whom the biomarker levels are stable or falling: The CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above from the most recent pre-procedure level.
- In patients with elevated CK-MB (or cTn) in whom the biomarker levels have not been shown to be stable or falling: The CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above plus new ST-segment elevation or depression plus signs consistent with a clinically relevant MI, such as new onset or worsening heart failure or sustained hypotension.

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# B. Accountability of PMA Cohort

At the time of database lock, of 1919 patients enrolled in the PMA study,  $96.7\%$  (1856/1919) patients are available for analysis at the completion of the study, the 12 month post-operative visit.

A total of 4206 patients signed the Informed Consent Form (IFC), of which 2263 were screen failures. In total, 1943 patients were randomized; 974 to  $\mathrm{EluNIR^{TM}}$  and 969 to Resolute, respectively. For 24 patients; 16 in the  $\mathrm{EluNIR}$  arm and eight (8) in the Resolute arm, the study stent was not advanced beyond the guiding catheter and the patients were de-registered from the study prior to being implanted with the study stent, leaving 1919 patients enrolled for the study. Twenty-one (21) deaths were reported in the study within the first 12 months (+14 days) after the Baseline procedure; 11 (1.1%) in the  $\mathrm{EluNIR^{TM}}$  arm, and 10 (1%) in the Resolute arm. Seven (7) patients, five (5) (0.5%) in the  $\mathrm{EluNIR^{TM}}$  arm, and two (2) (0.2%) in the Resolute arm, withdrew consent, and 21 patients, 11 (1.1%) in the  $\mathrm{EluNIR^{TM}}$  arm, and 10 (1%) in the Resolute arm, were lost to follow-up within the first 12 months (+14 days) after then Baseline procedure. Table 9 presents the overall disposition of subjects by treatment including reasons for discontinuations.

Table 9: Subject Disposition

|  Parameter | Statistic | EluNIR | Resolute | Overall  |
| --- | --- | --- | --- | --- |
|  Signed Informed Consent | n |  |  | 4206  |
|  Screen Failure | n |  |  | 2263  |
|  Randomized | n | 974 | 969 | 1943  |
|  De-registered | n | 16 | 8 | 24  |
|  Enrolled (Full Analysis Set) | n | 958 | 961 | 1919  |
|  Discontinued | % (n/N) | 1.8%(17/958) | 1.2%(12/961) | 1.5%(28/1919)  |
|  Reason for Discontinuation: |  |  |  |   |
|  Subject withdrew consent | % (n/N) | 0.5%(5/958) | 0.2%(2/961) | 0.4%(7/1919)  |
|  Physician Withdrew Subject | % (n/N) | 0.1%(1/958) | 0.0%(0/961) | 0.1%(1/1919)  |
|  Lost to follow-up | % (n/N) | 1.1%(11/958) | 1.0%(10/961) | 1.1%(21/1919)  |
|  Death | % (n/N) | 1.1%(11/958) | 1.0%(10/961) | 1.1%(21/1919)  |

# C. Study Population Demographics and Baseline Characteristics

The demographics of the study population are typical for a pivotal study performed in the…

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**Source:** [https://fda.innolitics.com/device/P170008](https://fda.innolitics.com/device/P170008)

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